WO2003051850A1 - Composes de la pyrazine et compositions pharmaceutiques les contenant - Google Patents

Composes de la pyrazine et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO2003051850A1
WO2003051850A1 PCT/GB2002/005736 GB0205736W WO03051850A1 WO 2003051850 A1 WO2003051850 A1 WO 2003051850A1 GB 0205736 W GB0205736 W GB 0205736W WO 03051850 A1 WO03051850 A1 WO 03051850A1
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WO
WIPO (PCT)
Prior art keywords
pyrazinecarboxamide
disorders
bis
piperidinyl
compound
Prior art date
Application number
PCT/GB2002/005736
Other languages
English (en)
Inventor
Johan Michael Wilsterman
Anna Ingrid Kristina Berggren
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to AU2002352420A priority Critical patent/AU2002352420A1/en
Publication of WO2003051850A1 publication Critical patent/WO2003051850A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to certain pyrazine carboxamide compounds of formula I, to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
  • Cl modulators are useful in the treatment of obesity, psychiatric and neurological disorders (WO01/70700 and EP 656354).
  • CBt modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.
  • Pyrazinecarboxamides are reported to possess antithrombotic properties (WO 92/ 02513).
  • 5,6-Diphenyl-2-pyrazinecarboxylic acid is disclosed in CH 458 361.
  • the invention relates to compounds of the general formula (I)
  • R 1 represents cyclohexyl, 1-piperidinyl or phenyl; R represents H, chloro, bromo, methyl or methoxy; and when R 3 represents H, R 4 represents H or chloro; and when R 3 represents chloro, R 4 represents H or chloro.
  • R 1 represents cyclohexyl
  • R 1 represents 1-piperidinyl. In a third group of compounds of formula I, R 1 represents phenyl.
  • “Pharmaceutically acceptable salt”, where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts.
  • a suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates.
  • Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC.
  • the diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography.
  • stereoisomers may be made by chiral synthesis from chiral starting materials under conditions that will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention.
  • N,5,6-triphenyl-2-pyrazinecarboxamide N-phenyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;
  • the compounds of the invention may be prepared as outlined below according to any of the following methods. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the prior art.
  • R J NH 2 m in an inert solvent, for example dichloromethane, in the presence of a coupling agent, for example a carbodimide, eg l-(3-dimethylaminopropyl)-3-ethylcarbodiimide , and optionally in the presence of a catalyst, for example a basic catalyst, eg 4-dimethylamino- pyridine, at a temperature in the range of -25°C to 150°C.
  • a coupling agent for example a carbodimide, eg l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • a catalyst for example a basic catalyst, eg 4-dimethylamino- pyridine
  • the compounds of the invention may be isolated from their reaction mixtures using conventional techniques. Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
  • inert solvent refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • the compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other i ⁇ jectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient, or a pharmaceutically acceptable organic or inorganic addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.
  • a compound of the invention may also be combined with other anti-obesity agents such as Orlistat or a monoamine reuptake inhibitor, for example Sibutramine.
  • a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.
  • a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • the compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders(e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease.
  • the compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea).
  • the compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, ***e, opiates, etc) dependence and/or treating drug (nicotine, ethanol, ***e, opiates, etc) withdrawal symptoms.
  • the compounds may also eliminate the increase in weight which normally accompanies the cessation of smoking.
  • the present invention provides a compound of formula I as claimed in any previous claim for use as a medicament.
  • the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio- depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g.
  • diarrhea and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, ***e, opiates, etc) dependence and/or treating drug (nicotine, ethanol, ***e, opiates, etc) withdrawal symptoms.
  • treating drug e.g. treating drug (nicotine, ethanol, ***e, opiates, etc) dependence and/or treating drug (nicotine, ethanol, ***e, opiates, etc) withdrawal symptoms.
  • the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g.
  • psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions
  • neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis
  • treating drug (nicotine, ethanol, ***e, opiates, etc) dependence and/or treating drug (nicotine, ethanol, ***e, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.
  • the compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.
  • Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS).
  • 1H NMR measurements were performed on either a Narian Mercury 300 or a Narian Inova 500, operating at 1H frequencies of 300 and 500 MHz respectively. Chemical shifts are given in ppm with CDC1 3 as internal standard.
  • Purification was performed on a semipreparative HPLC with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19 x 100 mm C8 column. The mobile phase used was, if nothing else is stated, acetonitrile and buffer (0.1 M NT ⁇ Ac: acetonitrile 95:5).
  • Example 1 N-(l-piperidinyl)- 5,6-diphenyl-2-pyrazinecarboxamide 5,6-Diphenylpyrazine-2-carboxylic acid (500 mg, 1.81 mmol) from Preparation A, step (a), was dissolved in DCM (4 ml) and DMF (150 ⁇ l). DMAP (22 mg, 0.18 mmol) and 1- aminopiperidine (218 mg, 2.17 mmol) were added and the solution was cooled to 0 °C. A slurry of EDC (1.99 mmol, in 2mL DCM and 100 ⁇ l DMF) was added dropwise. The reaction mixture was stirred at 25 °C.
  • N-cyclohexyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide 5,6-Di- -tolyl-pyrazine-2-carboxylic acid (76 mg, 0.25 mmol) from Preparation A, step (c), was used as described in Example 7.
  • Semipreparatory HPLC (0.01% TEA in the buffer phase) gave the subtitle compound (4 mg, 4%).
  • N-cvclohexyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide 5,6-Bis-(4-methoxyphenyl)-pyrazine-2-carboxylic acid (76 mg, 0.25 mmol) from Preparation A, step (d), was used essentially as described in Example 7 but the reaction mixture was first stirred overnight, then more cyclohexylamine (25 mg, 0.25 mmol) was added and the mixture was stirred for an additional two days prior to workup.
  • step (a) To 5,6-Diphenyl-pyrazine-2-carboxylic acid (70 mg, 0.25 mmol) from Preparation A, step (a), DMAP (0.025 mmol, in 0.5 ml DCM), aniline (0.25 mmol, in 1 ml DCM ), EDC (0.28 mmol, in 1ml DCM, cooled to 8 °C) and DMF (100 ⁇ l) were added. The reaction mixture was stirred at 25 °C over night, then worked up as described in Example 2. Semipreparatory HPLC (0.15 % TFA/water: acetonitrile 95:5 instead of the buffer phase) gave the title compound (27 mg, 30%) after washing with ⁇ a 2 CO 3 solution.
  • step (e) was used as described in Example 13, to give the subtitle compound (6 mg,
  • Example 18 (a) N-(l-piperidinyl - 5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-pyrazinecarboxamide The titled compound was isolated from the mixture prepared in Example 18 (35 mg) by preparative chromatography (9 mg, 26%). 1H ⁇ MR (300 MHz) ⁇ 9.46 (s, IH), 8.38 (s, IH), 7.46-7.24 (m, 7H), 2.89 (t, 4H), 1.78 (p, 4H), 1.52-1.40 (m, 2H).
  • Compounds of the present invention are active against the receptor product of the CB1 gene.
  • the affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al , Molecular Pharmacology, 1988, 34,605 or those described in WO01/70700 or EP 656354.
  • the assay may be performed as follows.
  • lO ⁇ g of membranes prepared from cells stably transfected with the CB 1 gene were suspended in 200 ⁇ l of lOOmM NaCl, 5mM MgCl 2 , ImM EDTA, 50mM HEPES (pH 7.4), ImM DTT, 0.1% BSA and lOO ⁇ M GDP.
  • an EC80 concentration of agonist CP55940
  • the required concentration of test compound and O.l ⁇ Ci [ 35 S]-GTP ⁇ S. The reaction was allowed to proceed at 30°C for 45 min.
  • the compounds of the present invention are active at the CB1 receptor (IC50 ⁇ 1 micromolar). Most preferred compounds have IC50 ⁇ 200 nanomolar.

Abstract

L'invention concerne un composé de formule (I) et ses sels pharmaceutiquement acceptable, ses solvates, et ses formes cristallines. Dans ladite formule, R1 représente cyclohéxyle, 1-pipéridinyle ou phényle ; R2 représente H, chlore, brome, méthyle ou méthoxy et quand R3 représente H, R4 représente H ou chlore ; quand R3 représente chlore, R4 représente H ou chlore. L'invention concerne également des procédés de préparation desdits composés, leur utilisation dans le traitement de l'obésité, de troubles psychiatriques et neurologiques en particulier l'obésité, ainsi que des compositions pharmaceutiques les contenant.
PCT/GB2002/005736 2001-12-19 2002-12-18 Composes de la pyrazine et compositions pharmaceutiques les contenant WO2003051850A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002352420A AU2002352420A1 (en) 2001-12-19 2002-12-18 Pyrazine compounds and pharmaceutical compositions containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0104332-2 2001-12-19
SE0104332A SE0104332D0 (sv) 2001-12-19 2001-12-19 Therapeutic agents

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SE (1) SE0104332D0 (fr)
TW (1) TW200410693A (fr)
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Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004111038A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide
WO2004111033A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Agents therapeutiques
WO2004111039A1 (fr) * 2003-06-19 2004-12-23 Astrazeneca Ab Utilisation de derives de 5,6-diaryl-pyrazine 2,3-substituee comme modulateurs du recepteur cannabinoide 1
WO2004111034A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Derives de 2-carboxamide et 2-sulfonamide-5,6-diaryl-pyrazine substitues en 3, utilises comme modulateurs de cb1
WO2005007628A1 (fr) 2003-07-11 2005-01-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
WO2006050842A1 (fr) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Derives dibenzosuberone
WO2006113704A2 (fr) * 2005-04-18 2006-10-26 Neurogen Corporation Antagonistes cb1 heteroaryle substitue
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7144890B2 (en) 2004-01-28 2006-12-05 Hoffman-La Roche Inc. Spiro-pentacyclic compounds
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7229999B2 (en) 2005-04-06 2007-06-12 Hoffmann-La Roche Inc. Pyridine-3-carboxamide derivatives as CB1 inverse agonists
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
WO2007084450A2 (fr) * 2006-01-18 2007-07-26 Schering Corporation Modulateurs de recepteurs de cannibinoides
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
WO2007147746A1 (fr) * 2006-06-19 2007-12-27 F. Hoffmann-La Roche Ag Dérivés de 2-pyrazinecarboxamide
US7326706B2 (en) 2003-08-15 2008-02-05 Bristol-Myers Squibb Company Pyrazine modulators of cannabinoid receptors
FR2904827A1 (fr) * 2006-08-11 2008-02-15 Sanofi Aventis Sa Derives de 5,6-bisaryl-2-pyridine-carboxamide, leur preparation et leur application en therapeutique comme antiganistes des recepteurs a l'urotensine ii
WO2008040651A1 (fr) 2006-10-04 2008-04-10 F. Hoffmann-La Roche Ag Dérivés de 3-pyridinecarboxamide et de 2-pyrazinecarboxamide utilisés en tant qu'agents augmentant le cholestérol hdl
WO2008081204A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes du gpcr de pipéridine
WO2008081206A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081207A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081208A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr pipéridiniques
WO2008081205A1 (fr) 2007-01-04 2008-07-10 Prosidion Limited Agonistes de gpcr de type pipéridine
US7405221B2 (en) 2002-09-27 2008-07-29 Merck & Co., Inc. Substituted pyrimidines
US7473693B2 (en) 2003-02-06 2009-01-06 Astrazeneca Ab Stable dispersion of solid particles comprising a water-insoluble pyrazine compound
US7517900B2 (en) 2003-10-10 2009-04-14 Bristol-Myers Squibb Company Pyrazole derivatives as cannabinoid receptor modulators
WO2009050523A1 (fr) 2007-10-18 2009-04-23 Prosidion Limited Agonistes du récepteur couplé à la protéine g de type azéditinyle
WO2009050522A1 (fr) 2007-10-18 2009-04-23 Prosidion Limited Agonistes du récepteur couplé a une protéine g de type azétidinyle
FR2927330A1 (fr) * 2008-02-07 2009-08-14 Sanofi Aventis Sa Derives de 5,6-bisaryl-2-pyridine-carboxamide, leur preparation et leur application en therapeutique comme antagonistes des recepteurs a l'urotensine ii
US7781593B2 (en) 2006-09-14 2010-08-24 Hoffmann-La Roche Inc. 5-phenyl-nicotinamide derivatives
US7780989B2 (en) 2002-07-18 2010-08-24 Astrazeneca Ab Process for the preparation of crystalline nano-particle dispersions
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
EP2308840A1 (fr) 2005-06-30 2011-04-13 Prosidion Limited Agonistes de GPCR
US8034949B2 (en) 2004-05-28 2011-10-11 Mitsubishi Tanabe Pharma Corporation Pyrrolidine compound and a process for preparing the same
WO2012032018A1 (fr) * 2010-09-09 2012-03-15 F. Hoffmann-La Roche Ag Hétéroarylméthyl-amides
US8410107B2 (en) 2010-10-15 2013-04-02 Hoffmann-La Roche Inc. N-pyridin-3-yl or N-pyrazin-2-yl carboxamides
US8669254B2 (en) 2010-12-15 2014-03-11 Hoffman-La Roche Inc. Pyridine, pyridazine, pyrimidine or pyrazine carboxamides as HDL-cholesterol raising agents

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US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
US7780989B2 (en) 2002-07-18 2010-08-24 Astrazeneca Ab Process for the preparation of crystalline nano-particle dispersions
US7405221B2 (en) 2002-09-27 2008-07-29 Merck & Co., Inc. Substituted pyrimidines
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7473693B2 (en) 2003-02-06 2009-01-06 Astrazeneca Ab Stable dispersion of solid particles comprising a water-insoluble pyrazine compound
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7354929B2 (en) 2003-04-23 2008-04-08 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
WO2004111038A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide
WO2004111034A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Derives de 2-carboxamide et 2-sulfonamide-5,6-diaryl-pyrazine substitues en 3, utilises comme modulateurs de cb1
WO2004111033A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Agents therapeutiques
WO2004111039A1 (fr) * 2003-06-19 2004-12-23 Astrazeneca Ab Utilisation de derives de 5,6-diaryl-pyrazine 2,3-substituee comme modulateurs du recepteur cannabinoide 1
US7884113B2 (en) 2003-07-11 2011-02-08 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
WO2005007628A1 (fr) 2003-07-11 2005-01-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
WO2005007111A2 (fr) 2003-07-11 2005-01-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
US7276608B2 (en) 2003-07-11 2007-10-02 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
US8119808B2 (en) 2003-07-11 2012-02-21 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
US7326706B2 (en) 2003-08-15 2008-02-05 Bristol-Myers Squibb Company Pyrazine modulators of cannabinoid receptors
US7517900B2 (en) 2003-10-10 2009-04-14 Bristol-Myers Squibb Company Pyrazole derivatives as cannabinoid receptor modulators
US7144890B2 (en) 2004-01-28 2006-12-05 Hoffman-La Roche Inc. Spiro-pentacyclic compounds
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US8034949B2 (en) 2004-05-28 2011-10-11 Mitsubishi Tanabe Pharma Corporation Pyrrolidine compound and a process for preparing the same
WO2006050842A1 (fr) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Derives dibenzosuberone
US7220743B2 (en) 2004-11-09 2007-05-22 Hoffmann-La Roche Inc. Heterocyclic CB1 receptor antagonists
US7229999B2 (en) 2005-04-06 2007-06-12 Hoffmann-La Roche Inc. Pyridine-3-carboxamide derivatives as CB1 inverse agonists
WO2006113704A3 (fr) * 2005-04-18 2007-02-08 Neurogen Corp Antagonistes cb1 heteroaryle substitue
WO2006113704A2 (fr) * 2005-04-18 2006-10-26 Neurogen Corporation Antagonistes cb1 heteroaryle substitue
EP2308840A1 (fr) 2005-06-30 2011-04-13 Prosidion Limited Agonistes de GPCR
WO2007084450A3 (fr) * 2006-01-18 2007-11-08 Schering Corp Modulateurs de recepteurs de cannibinoides
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